Erythromycin & mechanism of action

Erythromycin is a protein synthesis inhibitor that binds to the 50S ribosomal subunit of the bacterial ribosome. It is found in the family of antibiotics known as the macrolides; and antibiotics in this group are generally protein synthesis inhibitors. Other macrolides include azithromycin and clarithromycin. Lincomycin and clindamycin are antibiotics that inhibit protein synthesis in bacteria but are not macrolides. The macrolides specifically block translocation reaction during protein synthesis in bacteria once they bind to the 50S ribosomal subunit.

SOURCES OF ERYTHROMYCIN

Macrolides are naturally-synthesized by Streptomyces species. Erythromycin is synthesized naturally from a strain of Streptomyces known as S. erythreus. Macrolides can also be semi-synthesized by the chemical modification of their general structure especially by the incorporation of a substituent group into the lactone ring (Figure 3); and this result in the formation of newer macrolides such as azithromycin and clarithromycin.

STRUCTURE OF ERYTHROMYCIN

The chemical structure of macrolides (erythromycin) contains large lactone rings that are linked through glycoside bonds with amino sugars. They generally possess a macrocyclic lactone structure (Figure 3). The macrolides structure is usually composed of a large-membered ring that comprises of about 13-15 carbon molecules which are chemically linked to sugar molecules by glycosidic bonds. The chemical structure of erythromycin is shown in Figure 4.

Figure 3: Structure of a macrolides antibiotic. Macrolides generally have a lactone ring. Macrolide antibiotics including erythromycin and clarithromycin share a common macrocyclic lactone ring structure and deoxy sugar residues.

Figure 4. Chemical structure of erythromycin.

       CLINICAL APPLICATION OF ERYTHROMYCIN

Macrolides including erythromycin, clarithromycin and azithromycin are used to treat a wide variety of infections caused by both Gram positive and Gram negative bacteria. Erythromycin is active against the causative agents of whooping cough (caused by Bordetella pertussis), pneumonia (caused by Streptococcus pneumoniae), diphtheria (caused by Corynebacterium diphtheriae), syphilis (caused by Treponema pallidum) and diarrhea (caused by Campylobacter species). They also have activity against mycoplasmas and Chlamydia species. Azithromycin and clarithromycin have broader activity than erythromycin (the first member of the macrolides); and they can also be used to treat some non-bacterial infections such as toxoplasmosis (caused by Toxoplasma gondii) as well as infections caused by mycobacteria.

SPECTRUM OF ACTIVITY OF ERYTHROMYCIN

Erythromycin and the macrolides are generally bacteriostatic in action, and they have broad spectrum of activity since they are active against both pathogenic Gram positive bacteria and Gram negative bacteria. Through generally bacteriostatic in action, macrolides can be bacteriocidal to some pathogenic Gram positive bacteria.

MECHANISM OR MODE OF ACTION

Erythromycin and the other macrolides generally inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit of the bacterial ribosome (particularly the 23S rRNA). Binding of the 50S ribosomal subunit by erythromycin inhibits protein elongation (usually mediated by the enzyme, peptidyl transferase); and this prevents translocation of the ribosome during protein synthesis. Translocation is the movement of some part of the ribosome (especially the mRNA) to other parts of the ribosome (e.g. tRNA) during protein synthesis. Erythromycin blocks the elongation of the polypeptide chain during synthesis when the reversibly bind to the 50S ribosomal subunit, and they are bacteriostatic in action.

       BACTERIAL RESISTANCE TO ERYTHROMYCIN

The resistance of pathogenic bacteria to the antibacterial onslaught of the macrolides (including erythromycin) could be due to the influx-efflux mechanism which prevents intracellular accumulation of the drug by actively pumping it out or alteration of the binding site of the antibiotic on the target organism. The alteration of the binding site of erythromycin on the target bacteria is usually mediated by the methylation of the 23S rRNA receptor, which prevents the binding by the antibiotic.

PHARMACOKINETICS OF ERYTHROMYCIN

Erythromycin is easily inactivated by the gastric acid in the GIT, and thus they are poorly absorbed by the body when administered orally. However, the macrolides (inclusive of erythromycin) are distributed widely in the body and they are excreted in urine. It is orally absorbed as stearate or estolate salt, and cerebrospinal fluid (CSF) penetration of erythromycin is poor. It is excreted via biliary and feacal route. Erythromycin is acid labile and the absorption of salt formulations of the drug from the gastrointestinal tract is variable. Thus, erythromycin needs to be administered 2 hrs before or after a meal. The non-salt (base) form of erythromycin is not well absorbed when taken orally, and is used thus for sterilizing the gut before surgery.

       SIDE EFFECT/TOXICITY OF ERYTHROMYCIN

The clinical usage of erythromycin and other macrolides is usually associated with some undesirable untoward effects such as mild stomach or GIT upset, vomiting, fever, and diarrhea. Macrolides are generally nontoxic antibacterial agents.

REFERENCES

Denyer S.P., Hodges N.A and Gorman S.P (2004). Hugo & Russell’s Pharmaceutical Microbiology. 7th ed. Blackwell Publishing Company, USA. Pp.152-172.

Drusano G.L (2007).  Pharmacokinetics   and   pharmacodynamics   of   antimicrobials.  Clin   Infect   Dis, 45(suppl):89–95.

Ashutosh Kar (2008). Pharmaceutical Microbiology, 1st edition. New Age International Publishers: New Delhi, India.

Axelsen P. H (2002). Essentials of Antimicrobial Pharmacology. Humana Press, Totowa, NJ.

Murray P.R, Baron E.J, Jorgensen J.H., Pfaller M.A and Yolken R.H (2003). Manual of Clinical Microbiology. 8th edition. Volume 2. American Society of Microbiology (ASM) Press, Washington, D.C, U.S.A.

Murray P.R, Baron E.J, Jorgensen J.H., Pfaller M.A and Yolken R.H (2003). Manual of Clinical Microbiology. 8th edition. Volume 1. American Society of Microbiology (ASM) Press, Washington, D.C, U.S.A.

Murray P.R., Rosenthal K.S., Kobayashi G.S., Pfaller M. A. (2002). Medical Microbiology. 4th edition. Mosby Publishers, Chile.

Prescott L.M., Harley J.P and Klein D.A (2005). Microbiology. 6th ed. McGraw Hill Publishers, USA.

Mandell G.L., Bennett J.E and Dolin R (2000). Principles and practice of infectious diseases, 5th edition. New York: Churchill Livingstone.

Katzung, B. G.  (2003). Basic and Clinical Pharmacology (9th ed.). NY, US, Lange.

Hardman JG, Limbird LE, eds.  Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001.

Finch R.G, Greenwood D, Norrby R and Whitley R (2002). Antibiotic and chemotherapy, 8th edition. Churchill Livingstone, London and Edinburg.

 

 

 

Leave a Reply

Your email address will not be published. Required fields are marked *